Sekar Kathiresan (Verve)

Sekar Kathire­san show­cas­es his­toric mon­key da­ta in hunt for a once-and-done gene edit­ing ap­proach to pre­vent heart at­tacks

In a first for CRISPR — a field that’s seen quite a few his­toric moves in the past cou­ple of years — sci­en­tists have slashed cho­les­terol and lipid lev­els in mon­keys us­ing a tech­nique known as base edit­ing, gen­er­at­ing cru­cial proof-of-con­cept for both the biotech be­hind the ex­per­i­ment and a key part­ner.

Verve Ther­a­peu­tics de­signed two sim­i­lar ex­per­i­ments to test whether they can re­pro­duce pro­tec­tive mu­ta­tions in a pair of genes us­ing an ade­nine base ed­i­tor, which pre­cise­ly al­ters a cho­sen A to a G in the genome. CEO and co-founder Sekar Kathire­san pre­sent­ed the re­sults at a vir­tu­al keynote for the In­ter­na­tion­al So­ci­ety for Stem Cell Re­search over the week­end.

The base ed­i­tors ap­peared to have es­sen­tial­ly turned off genes, shut­ting down pro­duc­tion of cor­re­spond­ing pro­teins. That trans­lat­ed to a 60% drop in LDL with the PC­SK9 ther­a­py and a 64% plunge in triglyc­erides on the ANGPTL3 treat­ment.

When it comes to low­er­ing the col­lo­qui­al bad cho­les­terol, “60% is on par if not bet­ter than any oth­er treat­ment out there,” Kathire­san told End­points News just af­ter his pre­sen­ta­tion.

These re­sults are the cul­mi­na­tion of Kathis­er­an’s decades-long search for ge­net­ic clues for solv­ing coro­nary heart dis­ease, the lead­ing cause of death in the world. While di­rec­tor of the Cen­ter for Ge­nom­ic Med­i­cine at Mass­a­chu­setts Gen­er­al Hos­pi­tal and the Car­dio­vas­cu­lar Dis­ease Ini­tia­tive at the Broad In­sti­tute, he and col­leagues had iden­ti­fied eight genes that har­bor rare mu­ta­tions as­so­ci­at­ed with re­sis­tance to my­ocar­dial in­farc­tion. Af­ter show­ing in mice that they could ad­min­is­ter a one-time treat­ment for per­ma­nent low­er­ing of cho­les­terol, he left acad­e­mia to work on bring­ing it to hu­mans full-time.

There is, of course, still a long way to go. But Kathire­san be­lieves the new da­ta have lit up Verve’s path to the clin­ic.

They are still choos­ing be­tween the PC­SK9 and ANGPTL3 pro­grams as their lead can­di­date. Once they do — the dead­line will be the end of the year — an IND for pa­tients ge­net­i­cal­ly pre­dis­posed to high risk of heart at­tack is in sight for 2022.

Both pro­grams demon­strat­ed dra­mat­ic re­duc­tions in the tar­get pro­tein, cut­ting 89% of PC­SK9 and 95% of ANGPTL3 from the blood­stream. With the study lim­it­ed to two weeks, though, the dura­bil­i­ty ques­tions loomed large dur­ing the Q&A.

“We have en­cour­ag­ing da­ta out to sev­er­al months now,” Kathire­san said, ex­press­ing con­fi­dence that the edit­ing will be sta­ble long-term.

The rate of DNA reached 67% of the liv­er for PC­SK9 and 60% for ANGPTL3 which, Kathis­er­an point­ed out, rep­re­sents the ma­jor­i­ty of he­pa­to­cytes as around 30% of the liv­er is sup­port­ing tis­sue. Get­ting to not just ma­ture he­pa­to­cytes but al­so stem cells would be cru­cial. In pre­vi­ous re­search by oth­er groups, sci­en­tists have ob­served con­tin­ued edit­ing in mice cells even when they chop out parts of the liv­er and let it re­gen­er­ate.

Con­sid­er­ing the base ed­i­tors were de­ployed in vi­vo, safe­ty was al­so para­mount. Verve re­port­ed no off-tar­get ed­its in the 108 sites mea­sured — ow­ing, Kathire­san said, to the tech­nol­o­gy they have li­censed from Beam Ther­a­peu­tics.

Un­like the first gen­er­a­tion of CRISPR edit­ing, base edit­ing doesn’t snip at the site Cas9 brings it to; rather, through an en­zyme, it con­verts one base to an­oth­er chem­i­cal­ly.

“So it’s kind of in­ge­nious be­cause it us­es the GPS lo­cal­iza­tion fea­ture of Cas9, but it doesn’t use the dou­ble-strand break fea­ture of Cas9,” he said.

Apart from the mR­NA that forms the ed­i­tor, every Verve ther­a­py al­so con­sists of a guide RNA — picked out from hun­dreds — di­rect­ing the ma­chin­ery to the de­sired spot, all en­cap­su­lat­ed in a lipid nanopar­ti­cle en­gi­neered in col­lab­o­ra­tion with Van­cou­ver-based Acuitas.

De­liv­er­ing with lipid nanopar­ti­cles in­stead of a vi­ral vec­tor is a de­lib­er­ate choice.

“We need to get in, get the ed­i­tor and the guide RNA, get the edit­ing to hap­pen and then every­thing to go away as quick­ly as pos­si­ble,” Kathire­san said, “be­cause the longer the liv­er is ex­posed to the edit­ing ma­chin­ery, the more like­ly you are to get off-tar­get ef­fects. and lipid nanopar­ti­cles al­low de­liv­ery and then res­o­lu­tion of the process with­in a cou­ple of days.”

Al­so de­lib­er­ate is their de­ci­sion to part­ner wide­ly and as­sem­ble — not in­vent — all the tools that might aid their work. Base ed­i­tors aren’t go­ing to cov­er the full spec­trum of pos­si­ble and nec­es­sary changes as Kathire­san and his team go down their pri­or­i­tized list of eight genes. But they are tak­ing it one step at a time.

UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

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Sin­gu­lar fo­cus on ROR1 earns Velos­Bio $137M to fund PhI ADC and oth­er pro­grams

Years after selling Acerta to AstraZeneca for $7 billion, largely on the promise of its BTK inhibitor, Dave Johnson has once again gathered hefty financial support behind a new cancer target.

Matrix Capital Management and Surveyor Capital are leading a $137 million round for VelosBio, which has recently begun a Phase I study for its lead antibody-drug conjugate targeted against ROR1. Johnson took up the CEO post in October 2018.

Roger Tung, Concert Pharmaceuticals CEO (Concert)

Con­cert gets BTD for alope­cia drug, set­ting up a late-stage show­down with gi­ant ri­val Pfiz­er

Concert Pharmaceuticals’ path to developing a drug that treats alopecia areata has been bumpy, but the pharma company scored a win Wednesday.

The FDA granted Concert a Breakthrough Therapy Designation (BTD) for its oral Janus kinase inhibitor, named CTP-543, paving the way for a Phase III study of the drug to begin in the fourth quarter of 2020. The news follows positive Phase II results from last September, which saw the drug meet its primary endpoint in both 8 mg and 12 mg twice-daily doses.

Alexander Vos, VarmX CEO

'Fun­da­men­tal­ly dif­fer­en­t' from Por­to­la, Dutch biotech lands €32M to steer an­ti-an­ti­co­ag­u­lant through the clin­ic

Portola may not have had much success proving the commercial value of an anti-anticoagulant, but that’s not stopping European investors from pouring $36.2 million (€32 million) into what they see as a superior approach put forth by a Dutch biotech.

VarmX’s blood thinner reversal agent stems from research done by founder and CSO Pieter Reitsma at Leiden University Medical Center. A modified recombinant form of factor X, VMX-C001 “has an insertion of 16 amino acids that replaces a stretch of 7 amino acids in the so-called serine protease domain” compared to the native coagulation factor, CEO Alexander Vos told Endpoints News.

Covid-19 roundup: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

Adrian Gottschalk, Foghorn CEO

Mer­ck dan­gles up to $425 mil­lion to team with Flag­ship’s Foghorn Ther­a­peu­tics on drug­ging the shape of DNA

Two years after it first emerged from stealth mode, Flagship’s Foghorn Therapeutics has nabbed its first Big Pharma partner as Merck signs on to the biotech’s vision of drugging the very shape of DNA.

The deal, worth up to $425 million but with the upfront cash undisclosed, comes as Foghorn nears a pivot to a clinical stage biotech. The Cambridge-based company has added nearly 60 staffers from the 25 it had when it first emerged out of Flagship and, CEO Adrian Gottschalk said, they have finally refined the screening technology at the heart of the company, with plans to file their first IND towards the end of the year.

John Reed, Sanofi R&D chief (Endpoints News)

John Reed brings NK cells in­to Sanofi's CD38 ri­val­ry with J&J — and of­fers thumbs up for Kiadis' new fo­cus

Sanofi doesn’t just want to be a challenger to J&J’s dominant Darzalex multiple myeloma franchise. It’s looking to pioneer a new approach by pairing its own — newly approved — anti-CD38 drug with an NK cell therapy it’s just picked up.

The French pharma giant has teed up $19.7 million (€17.5 million) upfront and close to a billion dollars (€857.5 million) in milestones for a license to Kiadis Pharma’s preclinical K-NK004 program, which consists of NK cells that have been genetically engineered not to express CD38.

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